Squamous cell Carcinoma of the head and neck region (HNSCC) is the sixth most frequent cancer worldwide with an estimated 30,000 new cases and 8,000 deaths reported in the United States each year. Surgery and radiation are used to treat the primary tumor with chemotherapy reserved for disseminated disease. Unfortunately, there is a lack of transgenic HNSCC models with which to test new potential therapies. Traditional rodent models of HNSCC have relied on application of carcinogens to the hamster cheek pouch or xenografting of human cancer cells into immunodeficient mice. While these models have been useful, carcinogen exposure produces multiple DNA lesions which complicate the determination of which genetic events are required for HNSCC tumorigenesis. Xenograft studies do not replicate the early stages of carcinogenesis and are limited to human cancer cell lines that can proliferate in the murine environment. A key genetic event in most human cancer (including HNSCC) is mutation and inactivation of the tumor suppressor p53. This protein responds to DNA damage by inducing cell cycle arrest or apoptosis. The absence of functional p53 has been associated with tumor formation in mice. This proposal will develop two existing transgenic mouse strains in which p53 was inactivated by different mechanisms as animal models of HNSCC. The first model is the p53 null mutant mouse in which both alleles are inactivated by homologous recombination. The second model is the K14-HPV mouse in which the keratin 14 promoter directs expression of human papillomavirus early genes to the basal layer of oral mucosa. The HPV E6 gene product binds to and inactivates p53 protein. These models provide the advantage of monitoring turnorigenesis starting with a defined genetic lesion (i.e., p53 inactivation) and will prove very useful in future clinical and molecular studies of HNSCC.